1,5-Disubstituted imidazolid-4-ones

ABSTRACT

Compounds of the formula (I): ##STR1## wherein: Y is --CH 2  CH 2  --, --CH═CH-- or --C═C-- n is 1 to 5; 
     R 1  is hydrogen, or CO 2  R 1  represents an ester group in which the R 1  moiety contains from 1 to 12 carbon atoms; 
     R 2  is hydrogen, C 1-4  alkyl, trifluoromethyl, or phenyl; 
     R 3  is hydroxy or protected hydroxy; 
     R 5  is hydrogen, C 1-6  alkyl, phenyl or phenyl C 1-6  alkyl, any of which phenyl moieties may be substituted by one or more halogen, trifluoromethyl, C 1-6  alkyl, C 1-6  alkoxy or nitro groups; and 
     X is CH 2  and 
     R 4  is C 1-9  alkyl, C 3-8  cycloalkyl-C 1-6  alkyl, phenyl-C 1-6  alkyl or naphthyl-C 1-6  alkyl, any of which groups may have one acyclic carbon-carbon bond interrupted by an oxygen atom; hydrogen, C 3-8  cycloalky, phenyl or naphthyl, any of which phenyl of naphthyl moieties in R 4  may be substituted by one or more halogen, trifluoromethyl, C 1-6  alkyl, hydroxy, C 1-6  alkoxy or nitro groups; or 
     R 2  and R 4  taken with the carbon atom to which they are joined represent a C 5-8  cycloalkyl group; or 
     X is CS and 
     R 4  is C 1-9  alkyl, C 3-8  cycloalkyl-C 1-6  alkyl, phenyl-C 1-6  alkyl or naphthyl-C 1-6  alkyl, having one acyclic carbon-carbon bond interrupted by an oxygen atom, and in which any phenyl or naphthyl moieties may be substituted by one or more halogen, trifluoromethyl, C 1-6  alkyl, hydroxy, C 1-6  alkoxy or nitro groups; and salts thereof; having similar pharmacological activity to natural prostaglandins, processes for their preparation, intermediates useful in those processes and pharmaceutical compositions containing compounds of the formula (I).

This invention relates to novel compounds having pharmacologicalactivity, to a process for their preparation, to intermediates useful inthat process and to pharmaceutical compositions containing them.

German Offenlegungsschrift No. 2724948 discloses that compounds of thegeneral formula (A): ##STR2## wherein Z is hydrogen or alkyl; one of Z¹and Z² is a group --CH₂ --X--X¹ --X² in which X is phenylene,--CH.tbd.C--, cis- or trans --CH═CH-- or --CH₂ --CO₂ -- where eachradical Q independently of the other is hydrogen and/or alkyl or the tworadicals Q together are C₄₋₆ alkylene, X¹ is a covalent bond or astraight or branched C₁₋₆ alkylene chain, in which one methylene groupis optionally substituted by an oxa (--O--) group, with the proviso thatat least one carbon atom separates the oxa group from a --C.tbd.C--,--CH.tbd.CH-- or CO group, and X² is tetrazolyl, carboxyl, carboxamide,hydroxymethylene and/or alkoxycarbonyl; and the other one of Z¹ and Z²is a group -Y-Y¹ -Y² -Y³ in which Y is --CR₂ --CH₂ --, where eachradical R independently of the other is hydrogen and/or methyl, Y¹ iscarbonyl, methylene, methylene substituted by a hydroxy group ormethylene substituted by a hydroxy and alkyl group,

Y² is a covalent bond or straight-chain or branched C₁₋₇ alkyleneoptionally substituted on the carbon atom adjacent to Y¹ by one or twomutually independent alkyl, bicycloalkyl or cycloalkyl groups,

Y³ is hydrogen, hydroxy, C₁₋₇ (preferably C₁₋₄) alkoxy, cycloalkyl,bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy, where each phenyl,benzyl, phenoxy or benzyloxy group may be substituted in the benzenering by one or more hydroxy, halogen, nitro, amino, acylamino, alkenyl,alkoxy, phenyl and/or alkyl groups, which themselves may be substitutedone or more halogens, or

Y is a bond, --CH₂ -- or --CH₂.CH₂ -- and

Y¹, Y² and Y³ together are cycloalkyl which is substituted by a hydroxygroup which is preferably separated by 3 carbon atoms from the hydantoinring, have similar pharmacological activity to natural prostaglandins.

We have now discovered a class of compounds which have usefulpharmacological activity and which are structurally distinct from thecompounds disclosed in Offenlegungsschrift No. 2724948.

Accordingly, the present invention provides compounds of the formula(I): ##STR3## wherein: Y is --CH₂ CH₂ --, --CH.tbd.CH-- or --C.tbd.C-- nis 1 to 5;

R₁ is hydrogen, or CO₂ R₁ represents an ester group in which the R₁moiety contains from 1 to 12 carbon atoms;

R₂ is hydrogen, C₁₋₄ alkyl, trifluoromethyl, or phenyl;

R₃ is hydroxy or protected hydroxy;

R₅ is hydrogen, C₁₋₆ alkyl, phenyl or phenyl C₁₋₆ alkyl, any of whichphenyl moieties may be substituted by one or more halogen,trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkoxy or nitro groups; and

X is CH₂ and

R₄ is C₁₋₉ alkyl, C₃₋₈ cycloalkyl-C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl ornaphthyl-C₁₋₆ alkyl, any of which groups may have one acycliccarbon-carbon bond interrupted by an oxygen atom; hydrogen, C₃₋₈cycloalkyl, phenyl or naphthyl, any of which phenyl or naphthyl moietiesin R₄ may be substituted by one or more halogen, trifluoromethyl, C₁₋₆alkyl, hydroxy, C₁₋₆ alkoxy or nitro groups; or

R₂ and R₄ taken with the carbon atom to which they are joined representa C₅₋₈ cycloalkyl group; or

X is CS and

R₄ is C₁₋₉ alkyl, C₃₋₈ cycloalkyl-C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl ornaphthyl-C₁₋₆ alkyl, having one acyclic carbon-carbon bond interruptedby an oxygen atom; and in which any phenyl or naphthyl moieties may besubstituted by one or more halogen, trifluoromethyl, C₁₋₆ alkyl,hydroxy, C₁₋₆ alkoxy or nitro groups, and salts thereof.

Suitably Y is --CH₂ --CH₂ --.

Suitably n is 2, 3 or 4, preferably 3.

R₁ is hydrogen or CO₂ R₁ represents an ester group in which the R₁moiety contains from 1 to 12 carbon atoms. Examples of R₁ includehydrogen, methyl, ethyl, n- and iso- propyl, n-, sec- and tert-butyl,phenyl, benzyl, tolyl and the like, while normally hydrogen or C₁₋₆alkyl groups are preferred.

Suitably CO₂ R₁ can also represent an ester group which is readilyhydrolysable in vivo to give the free acid. Examples of R₁ in this caseinclude phthalidyl, pivaloyloxymethyl, 1-(ethoxycarbonyloxy)-ethyl andacetoxymethyl, more suitably phthalidyl.

Suitable examples of R₂ include hydrogen, methyl, ethyl and phenyl. Moresuitably R₂ is hydrogen, methyl, or ethyl, preferably methyl. R₂ mayalso be CF₃.

Suitable protected hydroxyl groups R₃ include readily hydrolysablegroups such as acylated hydroxy groups in which the acyl moiety contains1 to 4 carbon atoms, for example the acetoxy group; and hydroxyl groupsesterified by readily removeable inert groups such as the benzyl groupor like groups. Preferably R₃ is hydroxyl.

Suitable groups R₄ when R₄ is a C₁₋₉ alkyl group include C₄₋₉ alkylgroups. Such C₄₋₉ alkyl groups may be straight chain alkyl groups, suchas n-pentyl, n-hexyl and n-heptyl, or may be alkyl groups branched byone or two methyl groups (at the same or different carbon atoms). Thusfor example, R₄ may be a group CH₂ R₇, CH(CH₃)R₇ or C(CH₃)₂ R₇, whereinR₇ is a straight chain alkyl group such that the carbon content of theresultant group R₄ is 4 to 9.

In general preferred groups R₄ when R₄ is an alkyl group includestraight chain pentyl, hexyl and heptyl groups. Of these, straight chainhexyl is often the most useful. Other preferred groups R₄ include groupsCH(CH₃)R₇ and C(CH₃)₂ R₇ wherein R₇ is straight chain butyl, pentyl andhexyl.

Other suitable examples of R₄ when R₄ is an alkyl group include thelower alkyl groups, that is when R₄ is a C₁₋₄ alkyl group.

When R₄ is or contains a C₃₋₈ cycloalkyl moiety, the moiety may forexample be a cyclopropyl or cyclohexyl moiety. Examples of suitable C₁₋₆alkyl moieties when R₄ is a C₃₋₈ cycloalkyl --C₁₋₆ alkyl group includemethyl, ethyl, propyl, butyl and amyl.

When R₄ is an aryl group as preveiously defined, suitable groups R₄include phenyl, phenylmethyl, phenylethyl, phenyl n-propyl, phenyln-butyl, naphthyl, naphthyl-methyl, naphthyl-ethyl, naphthyl n-propyland naphthyl n-butyl, and such groups branched in the alkyl moiety byone or two methyl groups (at the same or different carbon atoms). Thesegroups may be substituted in the phenyl or naphthyl moiety by normallyone, two or three groups selected from those substituent groups listedhereinbefore. Examples of suitable substituent groups include fluorine,chlorine and bromine atoms and CF₃, methyl, ethyl, n- and iso-propyl,methoxy and ethoxy, n- and iso-propoxy and nitro groups. Other examplesof such groups include hydroxy. Preferably the aryl moieties whensubstituted by such groups will be mono or di-substituted.

When R₄ is a C₁₋₉ alkyl group interrupted by an oxygen atom, it may berepresented as a C₁₋₈ alkoxy-C₁₋₈ alkyl group containing of course nomore than 9 carbon atoms. Suitable examples of the alkyl moietiestherein are as described above for a C₁₋₉ alkyl R₄ group.

More suitably, R₄ alkyl groups interrupted by an oxygen have thestructure --CH₂ --(CH₂)j--O--(CH₂)_(k) --CH₃, optionally substituted byone or two methyl groups at the same or different carbon atoms, whereinj and k are each 0 to 3 and j+k is 3 to 5 and preferably 4. Preferably kis 0 or 1, so that a specific example of such a group is --(CH₂)₅--O--Me.

When R₄ is C₃₋₈ cycloalkyl-C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl ornaphthyl-C₁₋₆ alkyl in which one acyclic carbon-carbon bond isinterrupted by an oxygen atom, then it can suitably be a group offormula --CH₂ --(CH₂)_(m) --O--(CH₂)_(x) ---[cyclic moiety] optionallysubstituted by one or two methyl groups at the same or different acycliccarbon atoms, wherein m and x are 0 to 5 and m+x is no more than 5.

Also, R₂ and R₄ taken with the carbon atom to which they are joined canrepresent a C₅₋₈ cycloalkyl group, such as the cyclohexyl group.

Suitable examples of R₅ include hydrogen, methyl, ethyl, n- andiso-propyl, n-, sec- and tert-butyl; phenyl; phenylmethyl, phenethyl,phenyl-n-propyl, phenyl-n-butyl; and such phenylalkyl groups branched intheir alkyl moieties by one or two methyl groups (at the same ordifferent carbon atoms).

More suitably R₅ is C₁₋₆ alkyl such as methyl and ethyl, e.g. methyl.

When R₅ is or includes a phenyl moiety, it can optionally be substitutedas described above for R₄ aryl groups.

The compounds of the formula (I) may form conventional salts. Such saltsinclude those with alkali and alkaline earth metals, such as sodium andpotassium, and ammonium and substituted ammonium salts.

The compounds of the formula (I) may also form conventional acidaddition salts. Such salts include salts with pharmaceuticallyacceptable acids such as hydrochloric, hydrobromic, phosphoric, acetic,fumaric, salicylic, citric, lactic, mandelic, tartaric andmethane-sulphonic acid.

A group of compounds within the compounds of the formula (I) as definedare those wherein X is CH₂ and R₄ is C₁₋₉ alkyl, C₃₋₈ cycloalkyl-C₁₋₆alkyl, phenyl-C₁₋₆ alkyl or naphthyl-C₁₋₆ alkyl, any of which groups mayhave one acyclic carbon-carbon bond interrupted by an oxygen atom;hydrogen C₃₋₈ cycloalkyl, phenyl or naphthyl, any of which phenyl ornaphthyl moieties in R₄ may be substituted by one or more halogen,trifluoromethyl, C₁₋₆ alkyl, hydroxy, C₁₋₆ alkoxy or nitro groups; or R₂and R₄ taken with the carbon atom to which they are joined together aC₅₋₈ cycloalkyl group; and other variables are as defined in formula(I); and salts thereof.

From the aforesaid it will be seen that one particular suitablesub-group of compounds within formula (I) is of the formula (II):##STR4## wherein: Y, R₁ and R₅ are as defined in formula (I);

n¹ is 2, 3 or 4.

R₂ ¹ is hydrogen, methyl, ethyl or phenyl;

R₄ ¹ is hydrogen or C₁₋₉ alkyl; and salts thereof.

In formula (I) n¹ is preferably 3. Also Y is preferably --CH₂ CH₂ --.

R₂ ¹ is more suitably hydrogen, methyl or ethyl, preferably methyl.

While R₄ ¹ may be hydrogen or a C₁₋₉ alkyl group, it is normally a C₄₋₉alkyl group. In such cases suitable and preferred straight chain andbranched groups R₄ ¹ include those previously described as suitable andpreferred for the group R₄ when R₄ is a C₄₋₉ alkyl group. Such preferredgroups R₄ ¹ include straight chain pentyl, hexyl and heptyl, and ofthese normally the most useful is straight chain hexyl. Other preferredgroups R₄ ¹ include CH(CH₃)R₇ ¹ and C(CH₃)₂ R₇ ¹ wherein R₇ ¹ isstraight chain butyl, pentyl or hexyl.

Suitably R₅ is C₁₋₆ alkyl such as methyl and ethyl, preferably methyl.

A second sub-group of compounds within formula (I) of particularinterest are those of formula (III): ##STR5## wherein: Y, R₁ and R₅ areas defined in formula (I);

n¹ is 2, 3 or 4;

R₂ ¹ is hydrogen, methyl, ethyl or phenyl;

R₄ ² is a group of formula (IV): ##STR6## wherein T is a bond, or a C₁₋₆alkylene group which may be straight chain or branched by one or twomethyl groups at the same or different carbon atoms; and W, Y and Z areeach hydrogen or fluorine, chlorine or bromine atoms, or CF₃, methyl,ethyl, n- or iso-propyl, methoxy, ethoxy, n- or iso-propoxy or nitrogroups; and salts thereof.

In formula (III) n¹ is preferably 3. Also Y is preferably --CH₂ CH₂ --;

R₂ ¹ is more suitably hydrogen, methyl or ethyl, preferably methyl.

In formula (IV) often T will be a group --(CH₂)_(q) -- wherein q is 0 to4. Also, suitably W and Y are hydrogen.

Suitably R₅ is C₁₋₆ alkyl such as methyl and ethyl, preferably methyl.

A further sub-group of compounds within formula (I) of interest is offormula (V): ##STR7## wherein: Y, R₁ and R₅ are as defined in formula(I):

n¹ is 2, 3 or 4;

R₂ ¹ is hydrogen, methyl, ethyl or phenyl;

R₄ ³ is a group of formula (VI): ##STR8## wherein T is as defined informula (IV) and r is 0 to 3; and salts thereof.

In formula (V) n¹ is preferably 3. Also Y is preferably --CH₂ CH₂ --;

R₂ ¹ is more suitably hydrogen, methyl or ethyl, preferably methyl.

In formula (VI) often T will be a group --(CH₂)_(q) -- wherein q is 0 to4. Also suitably r is 1.

Suitably R₅ is C₁₋₆ alkyl such as methyl and ethyl, preferably methyl.

A further sub-group of compounds within formula (I) of interest is offormula (II) as defined, but wherein R₄ ¹ is a C₁₋₉ alkyl, C₃₋₈cycloalkyl-C₁₋₆ alkyl or phenyl-C₁₋₆ alkyl group in which groups oneacyclic carbon-carbon bond is interrupted by an oxygen atom and in whichany phenyl moiety may be optionally substituted as hereinbeforedescribed.

In this sub-group preferred R₄ groups include an alkyl group interruptedby oxygen which may be represented as a C₁₋₈ alkoxy-C₁₋₈ alkyl groupcontaining of course no more than 9 carbon atoms, as hereinbeforedescribed.

Another sub-group of compounds within formula (I) is of formula (VII):##STR9## wherein: R₄ ⁴ is C₁₋₉ alkyl, C₃₋₈ cycloalkyl-C₁₋₆ alkyl,phenyl-C₁₋₆ alkyl or naphthyl-C₁₋₆ alkyl, having one acycliccarbon-carbon bond interrupted by an oxygen atom; in which phenyl ornapthyl moieties may be substituted by one or more halogen,trifluoromethyl, C₁₋₆ alkyl, hydroxy, C₁₋₆ alkoxy or nitro groups; andthe remaining variables are as defined in formula (I).

Suitable and preferred variables other than R₄ ⁴ are as so describedbelow formula (I).

Suitable and preferred R₄ ⁴ are as so described under formula (I) for R₄having one acyclic carbon-carbon bond interrupted by an oxygen atom.

In the sub-groups hereinbefore described, R₁ is hydrogen or CO₂ R₁represents as ester group, in which the R₁ moiety contains from 1 to 12carbon atoms.

Preferably in the sub-groups R₁ is hydrogen, or a C₁₋₆ alkyl group.

However it is believed that in the sub-groups, compounds where CO₂ R₁ isan in vivo hydrolysable ester will also be of particular interest asready sources of the corresponding free acid. Examples of R₁ in eachcase include phthalidyl, pivaloyloxymethyl, 1-(ethoxycarbonyloxy)ethyland acetoxymethyl, more suitably phthalidyl.

It will of course be realised that the compounds of the formula (I) haveasymetric centres, and thus are capable of existing in a number ofstereoisomeric forms. The invention extends of each of thesestereoisomeric forms, and to mixtures thereof. The differentsteroisomeric forms may be separated one from the other by the usualmethods.

The present invention further provides a process for the preparation ofthe compounds of the formula (I), wherein X is CH₂, which processcomprises reducing a compound of the formula (IX): ##STR10## wherein R₄⁵ is as defined for R₄ when X=CH₂ is formula (I) and remaining groupsare as hereinbefore defined; and thereafter if desired or necessaryconverting Y, R₁, R₃ or a R₅ hydrogen in the compound thus formed intoanother Y, R₁, R₃ or R₅.

The reductive desulphurisation may be carried out in the presence of asuitably conventional hydrogenation catalyst, such as Raney nickel,under conventional conditions for such reactions. For example a solutionof the chosen compound of the formula (IX) in an organic solvent may beadded to a refluxing suspension of the catalyst in a similar solvent. Itwill be appreciated by the skilled man that when Y is --CH═CH-- or--C.tbd.C--, the reaction conditions must be selected having regard tothe reactivity of Y.

The present invention also provides a process for the preparation of thecompounds of the formula (I) wherein X is CS, i.e. the compounds of theformula (VII), which process comprises the cyclisation of a compound ofthe formula (VIII): ##STR11## wherein the variable groups are ashereinbefore defined.

Preparation of Intermediates

The same process may be used for the preparation of the intermediates ofthe formula (IX) by the cyclisation of a compound of formula (X):##STR12## wherein the variable groups are as hereinbefore defined informula (IX).

Either cyclisation may suitably be carried out by warming the compoundof the formula (VIII) or (X) alone, or by heating the compound of theformula (VIII) or (X) in an inert organic solvent such as benzene or thelike, suitably under reflux. When R₅ is hydrogen the solvent should benon-hydroxylic. In some cases the necessary cyclisation of the compoundof the formula (VIII) or (X) under these conditions can only be achievedin the presence of a strong base, such as sodium hydride or sodiumethoxide, in a dry organic solvent. This may be necessary when R₅ is asterically hindered group.

When R₅ is hydrogen, such compounds of the formula (VIII) or (X) can beprepared by reacting a salt M⁺ CNS⁻, wherein M⁺ is a metal ion, with acompound of the formula (XI) or (XII) respectively in the presence of anacid, e.g. by using a mineral acid such as aqueous hydrochloride acid,or a corresponding acid addition salt of the compound of the formula(XI) or (XII) respectively: ##STR13## wherein the variable groups are ashereinbefore defined. This reaction can conveniently be carried out atroom temperature. Suitably M⁺ is a sodium or potassium ion.

When both R₁ and R₅ are other than hydrogen in the compound of theformula (VIII) or (X), the compound of the formula (VIII) or (X) isconveniently prepared by the reaction of a compound of the formula (XI)or (XII) respectively with R₅ NCS wherein R₅ is not hydrogen in an inertorganic solvent such as benzene or the like, a preferred process of theinvention.

In this case the compound of the formula (VIII) or (X) is convenientlycyclised in situ, suitably under reflux in the organic solvent used. Thepresence of a strong base may be necessary as noted above.

Intermediates of the formulae (VIII) and (XI) are believed to be noveland form an aspect of the present invention.

The conversion of a compound of the formula (I), wherein Y, R₁, R₃ or R₅(when R₅ is hydrogen) is altered when desired or necessary, may beachieved in a conventional manner. The conversion of a compound offormula (I) wherein X=CS, i.e. a compound of formula (VIII), to acompound wherein X=CH₂, may be achieved in the manner hereinbeforedescribed for the conversion of a compound of the formula (IX) to acompound of the formula (I) wherein X=CH₂.

By way of example of such conversions the group R₁ in the compound ofthe formula (I) may be varied by conventional esterification and/orde-esterification.

Similary, it will be realised that when a compound is desired whereinCO₂ R₁ is an ester group which is readily hydrolysable in vivo to thefree acid it may be preferred to convert the group CO₂ R₁ to such anester group as a final reaction step.

Similarly, if desired compounds wherein Y is --C.tbd.C-- may be reducedto compounds wherein Y is --CH═CH-- in known manner. Suitably thisreaction is carried out using catalytic hydrogenation, such as Lindlarcatalysis.

When Y is --CH═CH--, it may be reduced to --CH₂ --CH₂ -- in knownmanner, suitably using catalytic hydrogenation such as transistion-metalcatalysis.

Protected R₃ hydroxyl moieties may be deprotected in conventionalmanner. For example when R₃ is a benzyloxy group, the benzyl group maybe removed by hydrogenolysis. Thus it may be seen that `protectedhydroxy` compounds of the formula (I) are useful intermediates in thepreparation of the corresponding `free hydroxy` compounds of the formula(I).

Also, when R₅ is hydrogen, compounds of the formula (I) may be convertedto corresponding compounds but with different R₅ values by conventionalsubstitution reactions with R₅ X wherein X is a displaceable group suchas a halide or other good leaving group. In such reactions it may benecessary to first convert the compound of the formula (I) to an alkalimetal salt of the R₅ hydrogen.

The skilled man will realise that in some cases substituting a R₅hydrogen will also substitute a R₁ hydrogen. Thus if a compound isdesired wherein R₁ is hydrogen and R₅ is substituted, in such cases itwill be preferred to esterify the R₁ hydrogen before the substitutionreaction, and then de-esterify after the substitution reaction, to givethe desired R₁ hydrogen compound.

When a compound of the formula (I) contains an acidic hydrogen atom,salts thereof may be prepared in a conventional manner by for examplereacting the compound of the formula (I) with the required base. Forsalts of compounds wherein R₅ is hydrogen, the base should be a strongbase such as for example sodium in an alcohol such as ethanol, or thelike.

Compounds of the formula (I) contain a basic nitrogen atom when X isCH₂, and acid addition salts thereof may be prepared in a conventionalmanner by for for example reacting the compound of the formula (I) withthe required acid.

Compounds of formula (XI) or (XII) may conveniently be prepared by aprocess which comprises reacting a compound of formula (XIII): R₁ O₂C--CH(Q₁)--CH₂ --Y--(CH₂)_(n) CO₂ R₁ with a compound of the formula(XIV): Q₂ (CH₂)₂ CR₂ R₃ R₄ ⁵ or (XV): Q₂ (CH₂)₂ CR₂ R₃ R₄ ⁴ in whichcompounds one of Q₁ and Q₂ is amino and the other of Q₁ and Q₂ is a goodleaving group, such as tosylate or a halide or like readily displaceablegroup. Preferred examples of such good leaving groups include bromide.

This displacement reaction is suitably carried out in an inert organicsolvent, such as hexamethylphosphoramide or N,N-dimethylformamide, atnon-extreme temperature, in the presence of a base, such as sodiumcarbonate or sodium hydride, and a source of alkali metal ions, such asan alkali metal halide. Suitable alkali halides include sodium iodideand lithium iodide.

Preparative procedures of this general nature for the synthesis ofcompounds of the formula (XI) or (XII) are described inOffenlegungsschriften Nos: 2552312, 2647969 and 2724948.

Compounds within the formula (I) have useful pharmacological activity.For example compounds within the formula (I) have anti-gastric secretionactivity e.g. anti-ulcer activity, cardiovascular activity, plateletaggregation inhibition activity, affect the respiratory tract e.g.bronchodilator activity, and have anti-fertility, smooth muscle andanti-arrhythmic activity.

In general it may be said that compounds within the formula (I) have arange of pharmacological activities similar to those shown by thenatural prostaglandins, but that these activities tend to be rather moreselective. The compounds of the formula (I) have particularly usefulbronchodilator activity.

The invention therefore also provides a pharmaceutical compositioncomprising a compound of the formula (I) and a pharmaceuticallyacceptable carrier.

Clearly the formulation of the said pharmaceutical composition willdepend on the nature of the activity shown by the chosen compound of theformula (I), and on other factors such as a preference in a particulararea of therapy for a particular mode of administration.

The compositions may be in the form of tablets, capsules, powders,granules, lozenges or liquid preparations, such as oral or sterileparenteral solutions of suspensions.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, fillers, tabletting lubricants, disintegrants, andacceptable wetting agents and the like. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilsuspensions, solutions, emulsions, syrups, or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives, andif desired conventional flavouring or colouring agents, and the like.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compounds of the formula (I) and a sterile vehicle. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved for injection and filter sterilized beforefilling into a suitable vial or ampoule and sealing. Advantageously,adjuvants such as a local anaesthetic, preservatives and bufferingagents can be dissolved in the vehicle. Parenteral suspensions areprepared in substantially the same manner except that the compound issuspended in the vehicle instead of being dissolved and sterilizationcannot be accomplished by filtration. The compound can be sterilized byexposure to ethylene oxide before suspending in the sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

When appropriate, the compositions of this invention may be presented asan aerosol for oral administration, or as a microfine powder forinsufflation.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

It will of course be realised that the precise dosage used in thetreatment of any of the hereinbefore described disorders will depend onthe actual compound of the formula (I) used, and also on other factorssuch as the seriousness of the disorder being treated.

The invention also provides a method of treatment and/or propylaxis ofdisorders in human beings and animals which comprises the administrationto the sufferer of an effective amount of a compound of the formula (I).

The following Examples 2 and 3 illustrate the preparation of compoundsof the formula (I) and their pharmacological properties.

EXAMPLE 1

Compound 1 ##STR14##

Dimethyl 2-[N-3'-hydroxy-3'-methyl-n-nonyl]aminoazelate (10 g) wasrefluxed with methyl isothiocyanate (1.89 g) in try toluene (100 ml) for3 hours. The toluene was evaporated in vacuo to give a yellow oil (11.1g). The oil was chromatographed on kieselgel (330 g) using chloroform aseluant to give1-(3'-hydroxy-3'-methyl-n-nonyl)-3-methyl-5-(6"-methoxycarbonyl-n-hexyl)-2-thiohydantoin(9.49 g) as a pale yellow oil.

The compounds shown in Table 1 were prepared in similar manner:

                  TABLE 1                                                         ______________________________________                                         ##STR15##                                                                    Compound                                                                      number   R.sub.1 R.sub.2 R.sub.4    R.sub.5                                                                             d                                   ______________________________________                                        2        CH.sub.3                                                                              CH.sub.3                                                                              Ph         CH.sub.3                                                                            6                                   3        CH.sub.3                                                                              CH.sub.3                                                                              CH(CH.sub.3)C.sub.4 H.sub.9                                                              CH.sub.3                                                                            6                                   4        CH.sub.3                                                                               ##STR16##       CH.sub.3                                                                            6                                     5        CH.sub.3                                                                              CH.sub.3                                                                              C.sub.2 H.sub.5                                                                          CH.sub.3                                                                            6                                   11       CH.sub.3                                                                              CH.sub.3                                                                              CH.sub.3   CH.sub.3                                                                            6                                   12       CH.sub.3                                                                              H       C.sub.2 H.sub.5                                                                          CH.sub.3                                                                            6                                   13       CH.sub.3                                                                              CH.sub.3                                                                               ##STR17## CH.sub.3                                                                            6                                   14       CH.sub.3                                                                              CH.sub.3                                                                              C.sub.5 H.sub.11                                                                         CH.sub.3                                                                            6                                   ______________________________________                                    

EXAMPLE 2

Compound 6 ##STR18##

1-(3'-hydroxy-3'-methyl-n-nonyl)-3-methyl-5-(6"-methoxy-carbonyl-n-hexyl)-2-thiohydantoin(3.3 g) in methanol (10 ml) was added, over five minutes, to a stirred,refluxing, suspension of Raney nickel [NICAT 101]* (c. 20 g) in methanol(100 ml); reflux was continued for thirty minutes. The hot suspensionwas filtered through kieselguhr and the residue was well washed withmethanol. The methanol solution was evaporated in vacuo and the residuewas dissolved in ether.

The ether solution was washed with water and dried and evaporated invacuo to give a yellow gum (2.4 g) which was purified via columnchromatography on silica gel using chloroform/1% methanol as eluant togive1-(3'-hydroxy-3'-methyl-n-nonyl)-3-methyl-5-(6"-methoxycarbonyl-n-hexyl)-4-imidazolidone(2.3 g) as a clear gum.

The compounds shown in Table 2 were produced in a similar manner.

                  TABLE 2                                                         ______________________________________                                         ##STR19##                                                                    Compound                                                                      Number   R.sub.1 R.sub.2 R.sub.4    R.sub.5                                                                             d                                   ______________________________________                                        7        CH.sub.3                                                                              CH.sub.3                                                                              Ph         CH.sub.3                                                                            6                                   8        CH.sub.3                                                                              CH.sub.3                                                                              CH(CH.sub.3)C.sub.4 H.sub.9                                                              CH.sub.3                                                                            6                                   9        CH.sub.3                                                                               ##STR20##       CH.sub.3                                                                            6                                     10       CH.sub.3                                                                              CH.sub.3                                                                              C.sub.2 H.sub.5                                                                          CH.sub.3                                                                            6                                   15       CH.sub.3                                                                              H       C.sub.2 H.sub.5                                                                          CH.sub.3                                                                            6                                   16       CH.sub.3                                                                              CH.sub.3                                                                              C.sub.5 H.sub.11                                                                         CH.sub.3                                                                            6                                   ______________________________________                                    

EXAMPLE 3

The compounds shown in Table 3 may be prepared in similar manner to thecompounds listed in Table 2 of Example 2, from the correspondingintermediate compounds 11 and 13.

                  TABLE 3                                                         ______________________________________                                         ##STR21##                                                                    Compound Number                                                                             R.sub.1 R.sub.2 R.sub.4                                                                             R.sub.5                                                                             d                                   ______________________________________                                        17            CH.sub.3                                                                              CH.sub.3                                                                              CH.sub.3                                                                            CH.sub.3                                                                            6                                   18            CH.sub.3                                                                              CH.sub.3                                                                               ##STR22##                                                                          CH.sub.3                                                                            6                                   ______________________________________                                    

    ______________________________________                                        CHARACTERISING DATA                                                           Compound 1 (The compound of Example 1)                                         ##STR23##                                                                    ______________________________________                                         I.R. (cm.sup.-1):                                                                        3510, [OH];                                                                   ##STR24##                                                         NMR (τ):                                                                             7.75, (m), [OH; CH.sub.2CO.sub.2 CH.sub.3 ];                                  6.8, (s), [NCH.sub.3 ];                                                       7 to 6.2, (m), [NCH.sub.2 ];                                                  6.35, (s), [CO.sub.2 CH.sub.3 ];                                              5.9, (m), [NCH].                                                   Analysis:  C.sub.22 H.sub.40 N.sub.2 O.sub.4 S                                requires:  C, 61.64; H, 9.41; N, 6.53; S, 7.48%                               found:     C, 61.71; H, 9.51; N, 6.54; S, 7.34%                               Mass Spec.:                                                                              C.sub.22 H.sub.38 N.sub.2 O.sub.3 S [m*-H.sub.2 O]                 requires:  410.2603                                                           found:     410.2610                                                           ______________________________________                                    

    ______________________________________                                        Compound 3                                                                     ##STR25##                                                                    ______________________________________                                        I.R. (cm.sup.-1):                                                                       ##STR26##                                                           NMR (τ):                                                                           7.95, (s), [OH];                                                              7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ];                                      ##STR27##                                                                     ##STR28##                                                                    6.4, (s), [CO.sub.2 CH.sub.3 ];                                                ##STR29##                                                           Mass Spec.:                                                                            C.sub.22 H.sub.38 N.sub.2 O.sub.3 S [m*-H.sub.2 O]                   requires:                                                                              410.2603                                                             found:   410.2645                                                             Analysis:                                                                              C.sub.22 H.sub.40 N.sub.2 O.sub.4 S                                  requires:                                                                              C, 61.64; H, 9.40; N, 6.53; S, 7.47                                  found:   C, 61.72; H, 9.25; N, 6.27; S, 7.6.                                  ______________________________________                                    

    ______________________________________                                        Compound 4                                                                     ##STR30##                                                                    ______________________________________                                        I.R. (cm.sup.-1):                                                                        : 3550, [OH];                                                                  ##STR31##                                                         NMR (τ):                                                                             7.8, (t) [CH.sub.2 CO.sub.2 CH.sub.3 ];                                       7.75, (s), [OH];                                                               ##STR32##                                                                     ##STR33##                                                                    6.4, (s), [CO.sub.2 CH.sub.3 ];                                               5.95, (t), [NCH];                                                  Mass Spec.:                                                                              C.sub.20 H.sub.32 N.sub.2 O.sub.3 S, (*m-H.sub.2 O)                requires:  380.2133                                                           found:     380.2124                                                           Analysis:  C.sub.20 H.sub.34 N.sub.2 O.sub.4 S                                requires:  C, 60.27; H, 8.59, N, 702; S, 8.04                                 found:     C, 60.15; H, 8.75; N, 7.01; S, 8.0                                 ______________________________________                                    

    ______________________________________                                        Compound 5                                                                     ##STR34##                                                                    ______________________________________                                         I.R. (cm.sup.-1):                                                                          3550, [OH]; 1750 (shoulder 1730)                                              ##STR35##                                                       NMR (τ): 7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ];                                     7.55, (s), [OH];                                                               ##STR36##                                                                     ##STR37##                                                                    6.4, (s), [CO.sub.2 CH.sub.3 ];                                               5.9, (m), [NCH];                                                 ______________________________________                                    

    ______________________________________                                        Compound 6 - (the compound of Example 2)                                       ##STR38##                                                                    ______________________________________                                         I.R. (cm.sup.-1):                                                                         3550, [OH]; 1740, (broad),                                                    ##STR39##                                                        NMR (τ):                                                                              7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ];                                      ##STR40##                                                                     ##STR41##                                                                    6.4, (s), [CO.sub.2 CH.sub.3 ];                                                ##STR42##                                                                     ##STR43##                                                                    6.1 to 5.5 (hump) [OH];                                           Mass Spec.: C.sub.22 H.sub.42 N.sub.2 O.sub.4, [m*],                          requires:   398.3145                                                          found:      398.3125                                                          ______________________________________                                    

    ______________________________________                                        Compound 7                                                                     ##STR44##                                                                    ______________________________________                                        I.R. (cm.sup.-1):                                                                           3450, [OH]; 1735, [CO.sub.2 CH.sub.3 ];                                       ##STR45##                                                       ______________________________________                                    

    ______________________________________                                        Compound 8                                                                     ##STR46##                                                                    ______________________________________                                        I.R. (cm.sup.-1):                                                                         3500 [OH]; 1740, [cO.sub.2 CH.sub.3 ]; 1710,                                  ##STR47##                                                         NMR (τ):                                                                             7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ];                                     7.5 to 6.8, (m), [NCH.sub.2 ];                                                7.2, (s), [NCH.sub.3 ];                                                       6.4, (s), [CO.sub.2 CH.sub.3 ];                                               6.3, [NCH];                                                                    ##STR48##                                                                    6.1 to 5.1, (hump), [OH];                                          ______________________________________                                    

    ______________________________________                                        Compound 9                                                                     ##STR49##                                                                    ______________________________________                                         I.R. (cm.sup.-1):                                                                        3500, [OH]; 1740, [CO.sub.2 CH.sub.3 ];                                       ##STR50##                                                         NMR (τ):                                                                             7.65, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ];                                      ##STR51##                                                                     ##STR52##                                                                    6.3, (s), (CO.sub.2 CH.sub.3 ];                                                ##STR53##                                                                     ##STR54##                                                                    6.1 to 5.6, (hump), [OH];                                          ______________________________________                                    

    ______________________________________                                        Compound 10                                                                    ##STR55##                                                                    ______________________________________                                        IR (cm.sup.-1):                                                                            3450, [OH]; 1740, [CO.sub.2 CH.sub.3 ];                                       ##STR56##                                                        N.M.R. (τ):                                                                           7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ];                                      ##STR57##                                                                     ##STR58##                                                                    6.4, (s), [CO.sub.2 CH.sub.3 ];                                                ##STR59##                                                                     ##STR60##                                                        Mass. Spec.:                                                                              C.sub.18 H.sub.34 N.sub.2 O.sub.4 [m*]                            requires:   342.2519                                                          found:      342.2555                                                          ______________________________________                                    

    ______________________________________                                        Compound 11                                                                    ##STR61##                                                                    ______________________________________                                        I.R. (cm.sup.-1):                                                                         ##STR62##                                                                    CO.sub.2 CH.sub.3 ]                                                NMR (τ):                                                                             7.75, (brm), [CH.sub.2 CO.sub.2 CH.sub.3 ];                                   7.45, (s), [OH];                                                               ##STR63##                                                                     ##STR64##                                                                    6.4, (s), [CO.sub.2 CH.sub.3 ];                                                ##STR65##                                                         Mass Spec.:                                                                              C.sub.17 H.sub.30 N.sub.2 O.sub.4 S [m*]                           requires:  358.1926                                                           found:     358.1956                                                           ______________________________________                                    

    ______________________________________                                        Compound 12                                                                    ##STR66##                                                                    ______________________________________                                        I.R. (cm.sup.-1):                                                                             3500, [OH]; 1740 (broad)                                                      ##STR67##                                                     NMR (τ):   7.7, (t), (CH.sub.2 CO.sub.2 CH.sub.3 ];                                       ##STR68##                                                                     ##STR69##                                                                    6.4, (s), [CO.sub.2 CH.sub.3 ];                                                ##STR70##                                                     Analysis:      C.sub.17 H.sub.30 N.sub.2 O.sub.4 S                            requires:      C, 56.96; H, 8.43; N, 7.81;                                                   S, 8.94%.                                                      found:         C, 57.07; H, 8.67; N, 7.66;                                                   S, 8.53%.                                                      Mass Spec.     C.sub.17 H.sub.30 N.sub.2 O.sub.4 S [M*].                      requires       358.1926.                                                      found          358.1894.                                                      ______________________________________                                    

    ______________________________________                                        COMPOUND 13                                                                    ##STR71##                                                                    ______________________________________                                        I.R (cm.sup.-1):                                                                              3470, [OH]; 1740 (broad),                                                     ##STR72##                                                     NMR (τ):   7.8, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ];                                      7.75, (bs), [OH];                                                              ##STR73##                                                                     ##STR74##                                                                    6.4, (s), [CO.sub.2 CH.sub.3 ];                                                ##STR75##                                                     Mass Spec:     C.sub.22 H.sub.36 N.sub.2 O.sub.3 S [M*H.sub.2 O];             requires:      408.2430                                                       found:         408.2437                                                       ______________________________________                                    

    ______________________________________                                        COMPOUND 14                                                                    ##STR76##                                                                    ______________________________________                                        I.R (cm.sup.-1):                                                                               3470, [OH]; 1740 (broad),                                                     ##STR77##                                                    NMR (τ):    7.85, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ];                                     7.75, (s), [OH];                                                               ##STR78##                                                                     ##STR79##                                                                    6.4, (s), [CO.sub.2 CH.sub.3 ];                                                ##STR80##                                                    Analysis:       C.sub.21 H.sub.38 N.sub.2 O.sub.4 S                           requires:       C, 60.85; H, 9.24; N, 6.76;                                                   S, 7.73%.                                                     found:          C, 60.51; H, 9.31; N, 6.35;                                                   S, 7.92%.                                                     Mass Spec.:     C.sub.21 H.sub.38 N.sub.2 O.sub.4 S [M*];                     requires:       414.2581                                                      found:          414.2565                                                      ______________________________________                                    

    ______________________________________                                        COMPOUND 15                                                                    ##STR81##                                                                    ______________________________________                                        I. R (cm.sup.-1):                                                                          3450, [OH]; 1740 [CO.sub.2 CH.sub.3 ];                                        ##STR82##                                                        NMR (τ):                                                                              7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ];                                      ##STR83##                                                                     ##STR84##                                                                     ##STR85##                                                                    6.3, (s), [CO.sub.2 CH.sub.3 ];                                                ##STR86##                                                        Mass Spec.: C.sub.17 H.sub.32 N.sub.2 O.sub.4 [M*].                           requires:   328.2362                                                          found:      328.2354.                                                         ______________________________________                                    

    ______________________________________                                        COMPOUND 16                                                                    ##STR87##                                                                    ______________________________________                                        I. R (cm.sup.-1):                                                                           3430, [OH]; 1735, [CO.sub.2 CH.sub.3 ];                                       ##STR88##                                                       NMR (τ): 7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ];                                      ##STR89##                                                                     ##STR90##                                                                     ##STR91##                                                                     ##STR92##                                                       ______________________________________                                    

PHARMACOLOGICAL DATA 1. Bronchodilation Activity

The compounds were examined for their ability to inhibit5-hydroxytryptamine or histamine induced bronchoconstristion in theanaesthetised, artifically respired guinea pig (Konzett-Rosslerpreparation). The compounds were administered intravenously. The resultsare shown in the Table.

    ______________________________________                                        Compound    ID50 against 5-hydroxytryptamine                                  Number      induced constriction g/Kg, i.v.                                   ______________________________________                                        6           30                                                                ______________________________________                                    

2. Anti-ulcer activity

Method

Anti-ulcer activity was assessed by the inhibition of indomethacininduced gastric damage in the rat according to the method of Eleghe(1974) Israeli J. Med. Sci. 10. 1451. Rats were starved overnight andgiven 15 mg/kg indomethacin subcutaneously and sacrificed 4 hours later.Stomachs were reflated with n. saline, cut along the greater curvaturepinned out and scored for gastric damage by the following system:

Score 1-3--according to degree of erythema and slight haemorrhage.

Score 4-6--according to degree of muscosal erosion.

Score 7-9--according to depth of gastric damage.

Groups of 7 rats were used for each treatment and the test compound orvehicle were administered 30 minutes prior to giving the indomethacin.Dose of test compound was 100 mg/kg orally and control groups receivingvehicle only were obtained using the above scoring system and the MannWitney test applied for significance of difference between the valuesobtained with the treatments.

The results are shown in the Table:

    ______________________________________                                                  Vehicle Control  Test Compound                                      Compound  Mean Score ± S.E.                                                                           Mean Score ±                                    Number    of Mean          S.E. of Mean                                       ______________________________________                                        6         3.71 ± 0.80   0.71 ± 0.42                                                                (P<0.01)                                           ______________________________________                                    

3. Toxcity

No toxic effects were observed at the test dosage.

I claim:
 1. A compound of the formula: ##STR93## the pharmaceuticallyacceptable acid addition salt thereof, and the alkali metal, alkalineearth metal, ammonium and substituted ammonium salt when R¹ ishydrogenwherein Y is --CH₂ CH₂ --, --CH═CH-- or --C.tbd.C--; n is 1 to5; R₁ is hydrogen, alkyl of 1 to 12 carbon atoms, phenyl, benzyl, tolyl,phthalidyl, pivaloyloxymethyl, 1-ethoxy-carbonyloxyethyl oracetoxymethyl; R₂ is hydrogen, alkyl of 1 to 4 carbon atoms,trifluoromethyl or phenyl; R₃ is hydroxy, alkanoyoxy of 1 to 4 carbonatoms or benzyloxy; R₅ is hydrogen, alkyl of 1 to 6 carbon atoms, phenylor phenylalkyl wherein alkyl has 1 to 6 carbon atoms, said phenyl andphenylalkyl being unsubstituted or substituted with one or more membersselected from the group consisting of halo, trifluoromethyl, alkyl of 1to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and nitro; and R₄,when taken alone, is (a) hydrogen; (b) unsubstituted alkyl of up to 9carbon atoms; (c) alkoxyalkyl of up to 9 carbon atoms; (d) cycloalkyl of3 to 8 carbon atoms; (e) phenyl; (f) naphthyl; (g) alkyl of up to 6carbon atoms substituted with cycloalkyl of 3 to 8 carbon atoms; (h)alkyl of up to 6 carbon atoms substituted with phenyl; (i) alkyl of upto 6 carbon atoms substituted with naphthyl; (j) --CH₂ (CH₂)_(m)--O--(CH₂)_(x) -cycloalkyl wherein each m and x have a value of from 0to 5 with the sum of m+x being no more than 5 and cycloalkyl containsfrom 3 to 8 carbon atoms; (k)--CH₂ (CH₂)_(m) --O--(CH₂)_(x) -phenylwherein m and x are as herein defined; or (1) --CH₂ (CH₂)_(m)--O--(CH₂)_(x) -naphthyl wherein m and x are as herein defined; any ofsaid phenyl or naphthyl being unsubstituted or substituted by one ormore members selected from the group consisting of halo,trifluoromethyl, alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6carbon atoms and nitro; or R₄, when taken with R₂, is alkylene of 4 to 7carbon atoms .
 2. A compound according to claim 1 and having theformula: ##STR94## the pharmaceutically acceptable acid addition saltthereof, and the alkali metal, alkaline earth metal, ammonium andsubstituted ammonium salt when R¹ is hydrogenwherein Y, R₁ and R₅ are astherein defined; n is 2, 3 or 4; R₂ is hydrogen, methyl, ethyl orphenyl; and R₄ is hydrogen or alkyl of 1 to 9 carbon atoms.
 3. Acompound according to claim 1 and having the formula: ##STR95## thepharmaceutically acceptable acid addition salt thereof, and the alkalimetal, alkaline earth metal, ammonium and substituted ammonium salt whenR¹ is hydrogenwherein Y, R₁ and R₅ are as therein defined; n is 2, 3 or4; R₂ is hydrogen, methyl, ethyl or phenyl; and R₄ is (a) unsubstitutedalkyl or alkoxyalkyl of up to 9 carbon atoms; (b) alkyl or alkoxyalkylof up to 6 carbon atoms substituted by cycloalkyl of 3 to 8 carbon atomsor phenyl, said phenyl being unsubstituted or substituted with one ormore members selected from the group consisting of halo,trifluoromethyl, alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6carbon atoms and nitro.
 4. A compound according to claim 1 and havingthe formula: ##STR96## the pharmaceutically acceptable acid additionsalt thereof, and the alkaline metal, alkaline earth metal, ammonium andsubstituted ammonium salt when R¹ is hydrogenwherein Y, R₁ and R₅ are astherein defined; n is 2, 3 or 4; R₂ is hydrogen, methyl, ethyl orphenyl; T is carbon-carbon bond or alkylene of 1 to 6 carbon atoms; andeach of W, Y and Z is independently hydrogen, fluoro, chloro, bromo,trifluoromethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy,propoxy, isopropoxy or nitro.
 5. A compound according to claim 1 andhaving the formula: ##STR97## the pharmaceutically acceptable acidaddition salt thereof, and the alkali metal, alkaline earth metal,ammonium and substituted ammonium salt when R¹ is hydrogenwherein Y, R₁and R₅ are as therein defined; n is 2, 3 or 4; R₂ is hydrogen, methyl,ethyl or phenyl; T is a carbon-carbon bond or alkylene of 1 to 6 carbonatoms; and r is 0, 1, 2 or
 3. 6. A compound according to claim 1 whereinn is
 3. 7. A compound according to claim 1 wherein Y is --CH₂ CH₂ --. 8.A compound according to claim 1 wherein R₁ is hydrogen or alkyl of 1 to6 carbon atoms.
 9. A compound according to claim 1 wherein R₂ ishydrogen or alkyl of 1 to 4 carbon atoms.
 10. A compound according toclaim 1 wherein R₃ is hydroxy.
 11. A compound according to claim 1wherein n R₄ is alkyl of 4 to 9 carbon atoms.
 12. A compound accordingto claim 1 wherein R₄ is phenyl or phenylalkyl, said phenyl andphenylalkyl being unsubstituted or substituted by halo, trifluoromethyl,alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or nitro.13. A compound according to claim 1 wherein R₄ is unsubstituted alkyl oralkoxyalkyl of up to 9 carbon atoms or alkyl or alkoxy of up to 6 carbonatoms substituted with cycloalkyl or phenyl, said phenyl beingunsubstituted or substituted with one or more members selected from thegroup consisting of halo, trifluoromethyl, alkyl of 1 to 6 carbon atoms,hydroxy, alkoxy of 1 to 6 carbon atoms and nitro.
 14. A compoundaccording to claim 2 wherein n is
 3. 15. A compound according to claim 2wherein Y is --CH₂ CH₂ --.
 16. A compound according to claim 2 whereinR₂ is methyl.
 17. A compound according to claim 2 wherein R₄ isn-pentyl, n-hexyl, n-heptyl.
 18. A compound according to claim 17wherein R₄ is hexyl.
 19. A compound according to claim 2 wherein R₄ ishex-2-yl; 2-methylhex-2-yl; hept-2-yl; 2-methylhept-2-yl; oct-2-yl or2-methyloct-2-yl.
 20. A compound according to claim 2 wherein R₅ ismethyl. 21.1-(3'-hydroxy-3'-methyl-n-nonyl)-3-methyl-5-(6"-methoxycarbonyl-n-hexyl)-4-imidazolidone.22. A compound according to claim 3 wherein R₄ is alkoxyalkyl of up to 9carbon atoms.
 23. A compound according to claim 4 wherein n is
 3. 24. Acompound according to claim 4 wherein Y is --CH₂ CH₂ --.
 25. A compoundaccording to claim 4 wherein R₂ is methyl.
 26. A compound according toclaim 4 wherein W and Y are each hydrogen.
 27. A compound according toclaim 4 wherein Y is a carbon-carbon bond or straight chained alkyleneof 1 to 4 carbon atoms.
 28. A compound according to claim 5 wherein n is3.
 29. A compound according to claim 5 wherein Y is --CH₂ CH₂ --.
 30. Acompound according to claim 5 wherein R₂ is methyl.
 31. A compoundaccording to claim 5 wherein T is a carbon-carbon bond or straightchained alkylene of 1 to 6 carbon atoms.
 32. A compound according toclaim 5 wherein r is
 1. 33. A compound according to claim 1 wherein R₂and R₄ taken together are alkylene of 4 to 7 carbon atoms.
 34. Acompound according to claim 33 wherein R₂ and R₄ taken together arepentamethylene.
 35. A pharmaceutical composition comprising an amount ofa compound according to claim 1 sufficient to effect a prostaglandinlike response and a pharmaceutically acceptable carrier.
 36. A method ofeffecting a prostaglandin like response in humans and domestic animals,which comprises the administration thereto of an effective amount of acompound according to claim 1.